Immediate and Long-Term Impact of Early-Life Trauma

早年创伤的直接和长期影响

• 批准号: 8244039
• 负责人: ANDREW M POULOS
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244039
• 关键词: Address; Adult; Age; Amnesia; Amygdaloid structure; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavioral; Biological; Biological Markers; Brain; Brain region; Characteristics; Child Abuse; Cognitive Therapy; Corticosterone; Cues; Development; Disease; Early-life trauma; Fright; Future; Gene Expression; Genes; Goals; Growth; Health; Hippocampus (Brain); Human; Immediate-Early Genes; Insulin-Like Growth Factor II; Knowledge; Laboratories; Learning; Life; Measures; Memory; Mental Depression; Mothers; Neural Pathways; Neurosecretory Systems; Nociception; Pain; Painless; Pathway interactions; Pharmacological Treatment; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Procedures; Process; Rattus; Regulation; Risk Factors; Rodent; Series; Shock; Staging; Stress; Stressful Event; System; Testing; Time; Tracer; Trauma; base; conditioned fear; cost; early childhood; experience; foot; functional status; infancy; insight; interest; maternal separation; mature animal; neural circuit; neuropeptide Y; pediatric trauma; physical abuse; postnatal; pup; relating to nervous system; response; social; stress resilience; stressor

DESCRIPTION (provided by applicant): Trauma during early childhood is a major risk factor for the adult development of anxiety disorders such as post-traumatic stress disorder (PTSD). Determining the underlying causes of this relationship has remained extraordinarily challenging. In particular, determining how the functional state of the brain at the time of trauma contributes to PTSD and its neural underpinnings remains an elusive goal. Prior efforts, using animal models have mainly focused on maternal-separation procedures as early life stressors. We propose the use of painful foot shocks as a trauma procedure given that it is a major component of child abuse. This procedure when presented at different post-natal ages has yielded important insights into the ontogeny of fear learning. Our laboratory has substantial experience in adult fear conditioning, with the above procedure in the mature animal resulting in a life-long memory of the trauma that depends on the amygdala (AMY), hippocampus (HIPP) and prefrontal cortex (PFC). Importantly, if this fear experience is strong enough it results in a sustained vulnerability to over-exaggerate fear responses even to mild reminders of the original trauma. This sensitized fear response is a central characteristic of PTSD. Our approach identifies 3 key hypotheses based on the timing of early life trauma (figure A): 1) Early Post-natal trauma during Stage 1: Prior to the functional maturation of AMY, fear learning systems cannot be sufficiently activated. 2) Middle Post-natal trauma during Stage 2: After the functional maturation of the AMY, but prior to the maturation of hippocampal context processing pathways, associative fear responses cannot be established, yet non-associative sensitization of fear and neuroendocrine responses persist. 3) Late Post-natal trauma during Stage 3: With the maturation of both systems both appropriate conditional responses can be acquired as well as a sustained adult enhancement of amygdala-based fear learning. To test these hypothesize we propose to identify the functional status of the fear neural circuits to early life trauma and how this contributes to development of adult PTSD related symptomology. This will be accomplished by using a neuroanatomical approach in which we are capable of characterizing the expression of immediately early genes within the amygdala and its associated afferent and efferent brain regions in response to repeated footshock trauma during early (P8), middle (P19) and late (P35) post-natal development. Next we address the long-lasting impact of trauma at these developmental time points on adult fear and neuroendocrine function. By understanding the how the maturing brain is susceptible to early-life trauma, this could provide great insight into mechanisms underlying a debilitating anxiety disorders such as PTSD.

描述（由申请人提供）：幼儿时期的创伤是成年后患焦虑症（如创伤后应激障碍（PTSD））的主要危险因素。确定这种关系的根本原因仍然极具挑战性。特别是，确定创伤时大脑的功能状态如何导致创伤后应激障碍及其神经基础仍然是一个难以实现的目标。之前使用动物模型的努力主要集中在将母亲分离程序作为早期生活压力源。我们建议使用痛苦的足部电击作为一种创伤治疗方法，因为它是虐待儿童的一个主要组成部分。这一过程在不同的产后年龄呈现，对恐惧学习的个体发育产生了重要的见解。我们的实验室在成人恐惧调节方面拥有丰富的经验，在成熟动物中进行上述程序会导致对创伤的终生记忆，这取决于杏仁核（AMY）、海马体（HIPP）和前额皮质（PFC）。重要的是，如果这种恐惧体验足够强烈，就会导致持续的脆弱性，过度夸大恐惧反应，甚至是对最初创伤的轻微提醒。这种敏感的恐惧反应是创伤后应激障碍的核心特征。我们的方法根据早期生活创伤的时间确定了 3 个关键假设（图 A）： 1）第一阶段的早期产后创伤：在 AMY 功能成熟之前，恐惧学习系统无法充分激活。 2）第二阶段的中期产后创伤：在AMY功能成熟之后，但在海马情境处理通路成熟之前，无法建立联想恐惧反应，但恐惧的非联想敏化和神经内分泌反应仍然存在。 3）第三阶段的晚期产后创伤：随着两个系统的成熟，可以获得适当的条件反应，并且成人基于杏仁核的恐惧学习持续增强。为了检验这些假设，我们建议确定早期生活创伤的恐惧神经回路的功能状态，以及这如何促进成人 PTSD 相关症状的发展。这将通过使用神经解剖学方法来实现，在该方法中，我们能够表征杏仁核及其相关传入和传出脑区域内立即早期基因的表达，以响应出生后发育早期（P8）、中期（P19）和晚期（P35）期间反复的足部休克创伤。接下来，我们讨论这些发育时间点的创伤对成人恐惧和神经内分泌功能的长期影响。通过了解成熟的大脑如何容易受到早年创伤的影响，这可以深入了解创伤后应激障碍（PTSD）等使人衰弱的焦虑症的潜在机制。